Project Summary The legal status and widespread use of alcohol among the US population is associated with adverse health outcomes in both adolescents and adults. Nearly 88% of the US population have used alcohol at least once during their lifetime and rates of binge drinking and heavy alcohol use continue to be of concern. Pharmacological treatments for alcohol abuse show limited effectiveness and only three medications are FDA approved for treating alcohol dependence. One factor that underlies this problem is a lack of understanding of the mechanisms that contribute to problem drinking. While many studies have revealed that alcohol excites midbrain dopamine neurons involved in reward-based behaviors, agents targeting dopamine have not been shown to be effective in reducing drinking. More recent studies have begun to investigate connections between higher brain areas such as the medial prefrontal cortex and orbitofrontal cortex and down-stream targets such as dorsal and ventral striatum, amygdala and hippocampus that are involved in the control of motivated behaviors. One key brain region that has largely been ignored in studies of alcohol consumption is the cerebellum that is known to communicate with cortical and reward-sensitive brain areas and is sensitive to both acute and chronic exposure to alcohol. In this proposal, we address this gap in our knowledge with experiments outlined under two Aims that explore how specific lobules of the cerebellum contribute to the regulation of ethanol drinking. Aim 1 uses models of homecage drinking and operant ethanol self-administration combined with lickometer circuitry to measure the amount, motivation and micro-structure of ethanol drinking in mice expressing DREADDs in selective cerebellar lobules. Control studies will examine whether DREADD-induced alterations in alcohol consumption are accompanied by motor deficits and concomitant changes in consumption of alternative rewards and tastants. Aim 2 uses slice electrophysiology to determine how DREADDs that affect ethanol drinking alter the firing of cerebellar Purkinje neurons and those in the deep cerebellar nuclei that are the sole output of the cerebellum. Neurons and regions outside the cerebellum affected by DREADD manipulation of ethanol drinking will be identified using the newly developed Fos-TRAP2 mice that permanently labels activated neurons during a brief window opened by tamoxifen injection. Results from these studies will provide the first comprehensive assessment of how cerebellar sub-regions contribute to alcohol drinking and will support the submission of a full- length R01 to continue this work.